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Mittersteiner M, Pereira GS, Wessjohann LA, Bonacorso HG, Martins MAP, Zanatta N. Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1 H)-ones Using 4-(Iodomethyl)pyrimidines. ACS OMEGA 2022; 7:18930-18939. [PMID: 35694463 PMCID: PMC9178747 DOI: 10.1021/acsomega.2c01925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/11/2022] [Indexed: 06/09/2023]
Abstract
This study reports two strategies for preparing O-alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1H)-ones: a linear protocol of alkylation, using a CCC-building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective O-alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70-98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.
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Affiliation(s)
- Mateus Mittersteiner
- Núcleo
de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
- Department
of Bioorganic Chemistry, Leibniz-Institute
of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
| | - Genilson S. Pereira
- Núcleo
de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
| | - Ludger A. Wessjohann
- Department
of Bioorganic Chemistry, Leibniz-Institute
of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
| | - Helio G. Bonacorso
- Núcleo
de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
| | - Marcos A. P. Martins
- Núcleo
de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
| | - Nilo Zanatta
- Núcleo
de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
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2
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Mittersteiner M, Pereira GS, Silva Y, Wessjohann LA, Bonacorso HG, Martins MAP, Zanatta N. Substituent-Driven Selective N-/ O-Alkylation of 4-(Trihalomethyl)pyrimidin-2(1 H)-ones Using Brominated Enones. J Org Chem 2022; 87:4590-4602. [DOI: 10.1021/acs.joc.1c02919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Mateus Mittersteiner
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
| | - Genilson S. Pereira
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Yuri Silva
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Ludger A. Wessjohann
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
| | - Helio G. Bonacorso
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Marcos A. P. Martins
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Nilo Zanatta
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
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3
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Mittersteiner M, Farias FFS, Bonacorso HG, Martins MAP, Zanatta N. Ultrasound-assisted synthesis of pyrimidines and their fused derivatives: A review. ULTRASONICS SONOCHEMISTRY 2021; 79:105683. [PMID: 34562732 PMCID: PMC8473776 DOI: 10.1016/j.ultsonch.2021.105683] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/12/2021] [Accepted: 07/20/2021] [Indexed: 06/09/2023]
Abstract
The pyrimidine scaffold is present in many bioactive drugs; therefore, efficient synthetic routes that provide shorter reaction times, higher yields, and site-selective reactions are constantly being sought. Ultrasound (US) irradiation has emerged as an alternative energy source in the synthesis of these heterocyclic scaffolds, and over the last ten years there has been a significant increase in the number of publications mentioning US in either the construction or derivatization of the pyrimidine core. This review presents a detailed summary (with 140 references) of the effects of US (synergic or not) on the construction and derivatization of the pyrimidine core through classical reactions (e.g., multicomponent, cyclocondensation, cycloaddition, and alkylation reactions). The main points that were taken into consideration are as follows: chemo- and regioselectivity issues, and the results of conventional heating methods compared to US and mechanistic insights that are also presented and discussed for key reactions.
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Affiliation(s)
- Mateus Mittersteiner
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil.
| | - Fellipe F S Farias
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
| | - Helio G Bonacorso
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
| | - Marcos A P Martins
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
| | - Nilo Zanatta
- Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil.
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4
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Xiao S, Tian Z, Wang Y, Si L, Zhang L, Zhou D. Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives. Med Res Rev 2018; 38:951-976. [PMID: 29350407 PMCID: PMC7168445 DOI: 10.1002/med.21484] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/14/2017] [Accepted: 12/16/2017] [Indexed: 12/20/2022]
Abstract
Viral infections cause many serious human diseases with high mortality rates. New drug‐resistant strains are continually emerging due to the high viral mutation rate, which makes it necessary to develop new antiviral agents. Compounds of plant origin are particularly interesting. The pentacyclic triterpenoids (PTs) are a diverse class of natural products from plants composed of three terpene units. They exhibit antitumor, anti‐inflammatory, and antiviral activities. Oleanolic, betulinic, and ursolic acids are representative PTs widely present in nature with a broad antiviral spectrum. This review focuses on the recent literatures in the antiviral efficacy of this class of phytochemicals and their derivatives. In addition, their modes of action are also summarized.
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Affiliation(s)
- Sulong Xiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Zhenyu Tian
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yufei Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Longlong Si
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Lihe Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Demin Zhou
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
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5
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He S, Li K, Lin B, Hu Z, Xiao J, Hu X, Wang AQ, Xu X, Ferrer M, Southall N, Zheng W, Aubé J, Schoenen FJ, Marugan JJ, Liang TJ, Frankowski KJ. Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle. J Med Chem 2017. [PMID: 28636348 DOI: 10.1021/acs.jmedchem.7b00561] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure-activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM. Lead compounds showed inhibition of the HCV pseudoparticle entry, suggesting a different mode of action from existing HCV drugs. Hit 7a and lead 7ii both showed synergistic effects in combination with existing HCV drugs. In vivo pharmacokinetics studies of 7ii showed high liver distribution and long half-life without obvious hepatotoxicity. The lead compounds are promising as preclinical candidates for the treatment of HCV infection and as molecular probes to study HCV pathogenesis.
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Affiliation(s)
- Shanshan He
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892-1800, United States
| | - Kelin Li
- University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States
| | - Billy Lin
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892-1800, United States
| | - Zongyi Hu
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892-1800, United States
| | - Jingbo Xiao
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Xin Hu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Amy Q Wang
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Xin Xu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Marc Ferrer
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Noel Southall
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Wei Zheng
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Jeffrey Aubé
- University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States
| | - Frank J Schoenen
- University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States
| | - Juan J Marugan
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892-1800, United States
| | - Kevin J Frankowski
- University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States
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6
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Yu F, Wang Q, Wang H, Si LL, Liu JX, Han X, Xiao SL, Zhang LH, Zhou DM. Synthesis and biological evaluation of echinocystic acid derivatives as HCV entry inhibitors. CHINESE CHEM LETT 2016. [DOI: 10.1016/j.cclet.2016.01.050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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7
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Sparks SM, Zhou H, Generaux C, Harston L, Moncol D, Jayawickreme C, Parham J, Condreay P, Rimele T. Identification of nonabsorbable inhibitors of the scavenger receptor-BI (SR-BI) for tissue-specific administration. Bioorg Med Chem Lett 2016; 26:1901-4. [PMID: 26988301 DOI: 10.1016/j.bmcl.2016.03.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 03/07/2016] [Accepted: 03/08/2016] [Indexed: 01/01/2023]
Abstract
The identification of a low-permeability scavenger receptor BI (SR-BI) inhibitor starting from the ITX-5061 template is described. Structure-activity and structure-permeability relationships were assessed for analogs leading to the identification of compound 8 as a potent and nonabsorbable SR-BI inhibitor.
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Affiliation(s)
- Steven M Sparks
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
| | - Huiqiang Zhou
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Claudia Generaux
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Lindsey Harston
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - David Moncol
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Channa Jayawickreme
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Janet Parham
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Patrick Condreay
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Thomas Rimele
- GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States
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8
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Talukdar R, Saha A, Ghorai MK. Domino-Ring Opening-Cyclization (DROC) of Donor-Acceptor (DA) Cyclopropanes. Isr J Chem 2016. [DOI: 10.1002/ijch.201500092] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Ranadeep Talukdar
- Department of Chemistry; Indian Institute of Technology Kanpur; Kanpur UP 208016 India
| | - Amrita Saha
- Department of Chemistry; Indian Institute of Technology Kanpur; Kanpur UP 208016 India
| | - Manas K. Ghorai
- Department of Chemistry; Indian Institute of Technology Kanpur; Kanpur UP 208016 India
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9
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Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection. Viruses 2015; 7:5659-85. [PMID: 26540069 PMCID: PMC4664971 DOI: 10.3390/v7112898] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 09/25/2015] [Accepted: 10/19/2015] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.
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Dockendorff C, Faloon PW, Germain A, Yu M, Youngsaye W, Nag PP, Bennion M, Penman M, Nieland TJF, Dandapani S, Perez JR, Munoz B, Palmer MA, Schreiber SL, Krieger M. Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 2015; 25:2594-8. [PMID: 25958245 DOI: 10.1016/j.bmcl.2015.03.074] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 12/01/2022]
Abstract
A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure-activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50=17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278.
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Affiliation(s)
- Chris Dockendorff
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA.
| | - Patrick W Faloon
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Andrew Germain
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Miao Yu
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Willmen Youngsaye
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Partha P Nag
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Melissa Bennion
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Marsha Penman
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Thomas J F Nieland
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Sivaraman Dandapani
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - José R Perez
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Benito Munoz
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Michelle A Palmer
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Stuart L Schreiber
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Monty Krieger
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
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11
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Dockendorff C, Faloon PW, Pu J, Yu M, Johnston S, Bennion M, Penman M, Nieland TJF, Dandapani S, Perez JR, Munoz B, Palmer MA, Schreiber SL, Krieger M. Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 2015; 25:2100-5. [PMID: 25900219 DOI: 10.1016/j.bmcl.2015.03.073] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 02/07/2023]
Abstract
We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure-activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50=0.10μM) and solubility (79μM in PBS), and it was designated as probe ML312.
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Affiliation(s)
- Chris Dockendorff
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA.
| | - Patrick W Faloon
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Jun Pu
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Miao Yu
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Stephen Johnston
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Melissa Bennion
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Marsha Penman
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Thomas J F Nieland
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
| | - Sivaraman Dandapani
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - José R Perez
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Benito Munoz
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Michelle A Palmer
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Stuart L Schreiber
- Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
| | - Monty Krieger
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
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12
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Vercauteren K, Mesalam AA, Leroux-Roels G, Meuleman P. Impact of lipids and lipoproteins on hepatitis C virus infection and virus neutralization. World J Gastroenterol 2014; 20:15975-91. [PMID: 25473151 PMCID: PMC4239485 DOI: 10.3748/wjg.v20.i43.15975] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 07/09/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infections represent a major global health problem. End-stage liver disease caused by chronic HCV infection is a major indication for liver transplantation. However, after transplantation the engrafted liver inevitably becomes infected by the circulating virus. Direct acting antivirals are not yet approved for use in liver transplant patients, and limited efficacy and severe side effects hamper the use of pegylated interferon combined with ribavirin in a post-transplant setting. Therefore, alternative therapeutic options need to be explored. Viral entry represents an attractive target for such therapeutic intervention. Understanding the mechanisms of viral entry is essential to define the viral and cellular factors involved. The HCV life cycle is dependent of and associated with lipoprotein physiology and the presence of lipoproteins has been correlated with altered antiviral efficacy of entry inhibitors. In this review, we summarise the current knowledge on how lipoprotein physiology influences the HCV life cycle. We focus especially on the influence of lipoproteins on antibodies that target HCV envelope proteins or antibodies that target the cellular receptors of the virus. This information can be particularly relevant for the prevention of HCV re-infection after liver transplantation.
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13
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Talukdar R, Tiwari DP, Saha A, Ghorai MK. Diastereoselective Synthesis of Functionalized Tetrahydrocarbazoles via a Domino-Ring Opening–Cyclization of Donor–Acceptor Cyclopropanes with Substituted 2-Vinylindoles. Org Lett 2014; 16:3954-7. [DOI: 10.1021/ol501763n] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Ranadeep Talukdar
- Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
| | - Deo Prakash Tiwari
- Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
| | - Amrita Saha
- Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
| | - Manas K. Ghorai
- Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
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Xiao S, Wang Q, Si L, Shi Y, Wang H, Yu F, Zhang Y, Li Y, Zheng Y, Zhang C, Wang C, Zhang L, Zhou D. Synthesis and anti-HCV entry activity studies of β-cyclodextrin-pentacyclic triterpene conjugates. ChemMedChem 2014; 9:1060-70. [PMID: 24623716 DOI: 10.1002/cmdc.201300545] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/19/2014] [Indexed: 01/11/2023]
Abstract
In our previous studies, oleanolic acid (OA) and echinocystic acid (EA), isolated from Dipsacus asperoides, were found to have anti-HCV entry properties. The major issue for members of this type of triterpene is their low water solubility. In this study, a series of new water-soluble triazole-bridged β-cyclodextrin (CD)-pentacyclic triterpene conjugates were synthesized via click chemistry. Thanks to the attached β-CD moiety, all synthesized conjugates showed lower hydrophobicity (Alog P) than their parent compounds. Several conjugates exhibited moderate anti-HCV entry activity. With the exception of per-O-methylated β-CD-pentacyclic triterpene conjugates, all other conjugates showed no cytotoxicity based on an alamarBlue assay carried out with HeLa, HepG2, MDCK, and 293T cells. More interestingly, the hemolytic activity of these conjugates disappeared upon the introduction of β-CDs. Easy access to such conjugates that combine the properties of β-CD and pentacyclic triterpenes may provide a way to obtain a new class of anti-HCV entry inhibitors.
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Affiliation(s)
- Sulong Xiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 (China).
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Yu F, Wang Q, Zhang Z, Peng Y, Qiu Y, Shi Y, Zheng Y, Xiao S, Wang H, Huang X, Zhu L, Chen K, Zhao C, Zhang C, Yu M, Sun D, Zhang L, Zhou D. Development of oleanane-type triterpenes as a new class of HCV entry inhibitors. J Med Chem 2013; 56:4300-19. [PMID: 23662817 DOI: 10.1021/jm301910a] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Development of hepatitis C virus (HCV) entry inhibitors represents an emerging approach that satisfies a tandem mechanism for use with other inhibitors in a multifaceted cocktail. By screening Chinese herbal extracts, oleanolic acid (OA) was found to display weak potency to inhibit HCV entry with an IC50 of 10 μM. Chemical exploration of this triterpene compound revealed its pharmacophore requirement for blocking HCV entry, rings A, B, and E, are conserved while ring D is tolerant of some modifications. Hydroxylation at C-16 significantly enhanced its potency for inhibiting HCV entry with IC50 at 1.4 μM. Further modification by conjugation of this new lead with a disaccharide at 28-COOH removed the undesired hemolytic effect and, more importantly, increased its potency by ~5-fold (54a, IC50 0.3 μM). Formation of a triterpene dimer via a linker bearing triazole (70) dramatically increased its potency with IC50 at ~10 nM. Mechanistically, such functional triterpenes interrupt the interaction between HCV envelope protein E2 and its receptor CD81 via binding to E2, thus blocking virus and host cell recognition. This study establishes the importance of triterpene natural products as new leads for the development of potential HCV entry inhibitors.
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Affiliation(s)
- Fei Yu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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Gataullin RR. Advances in the synthesis of cycloalka[b]indoles. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2013. [DOI: 10.1134/s1070428013020012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Wichroski MJ, Fang J, Eggers BJ, Rose RE, Mazzucco CE, Pokornowski KA, Baldick CJ, Anthony MN, Dowling CJ, Barber LE, Leet JE, Beno BR, Gerritz SW, Agler ML, Cockett MI, Tenney DJ. High-throughput screening and rapid inhibitor triage using an infectious chimeric Hepatitis C virus. PLoS One 2012; 7:e42609. [PMID: 22880053 PMCID: PMC3412796 DOI: 10.1371/journal.pone.0042609] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 07/09/2012] [Indexed: 12/14/2022] Open
Abstract
The recent development of a Hepatitis C virus (HCV) infectious virus cell culture model system has facilitated the development of whole-virus screening assays which can be used to interrogate the entire virus life cycle. Here, we describe the development of an HCV growth assay capable of identifying inhibitors against all stages of the virus life cycle with assay throughput suitable for rapid screening of large-scale chemical libraries. Novel features include, 1) the use of an efficiently-spreading, full-length, intergenotypic chimeric reporter virus with genotype 1 structural proteins, 2) a homogenous assay format compatible with miniaturization and automated liquid-handling, and 3) flexible assay end-points using either chemiluminescence (high-throughput screening) or Cellomics ArrayScan™ technology (high-content screening). The assay was validated using known HCV antivirals and through a large-scale, high-throughput screening campaign that identified novel and selective entry, replication and late-stage inhibitors. Selection and characterization of resistant viruses provided information regarding inhibitor target and mechanism. Leveraging results from this robust whole-virus assay represents a critical first step towards identifying inhibitors of novel targets to broaden the spectrum of antivirals for the treatment of HCV.
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Affiliation(s)
- Michael J. Wichroski
- Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, United States of America
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Discovery of ITX 4520: a highly potent orally bioavailable hepatitis C virus entry inhibitor. Bioorg Med Chem Lett 2012; 22:4955-61. [PMID: 22784640 DOI: 10.1016/j.bmcl.2012.06.038] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2012] [Revised: 06/10/2012] [Accepted: 06/12/2012] [Indexed: 01/20/2023]
Abstract
The manuscript reports an identification of a highly potent, orally bioavailable hepatitis C virus entry inhibitor through optimization of a previously reported class of molecules (1) that were not stable in the rat plasma. Compound 39 (ITX 4520) exhibited an excellent PK profile in both rats and dogs with good oral exposure, half-life and oral bioavailability. The compound is also well-tolerated in the preliminary in vivo toxicity studies and has been selected as a pre-clinical candidate for our HCV clinical pipeline.
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Vercauteren K, Leroux-Roels G, Meuleman P. Blocking HCV entry as potential antiviral therapy. Future Virol 2012. [DOI: 10.2217/fvl.12.47] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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